PROJECT SUMMARY Adolescents are an important vulnerable population to consider as the FDA moves toward a nicotine reduction policy. Such a policy, which would mandate a reduction of nicotine in all commercially available cigarettes, has the potential to transform public health and greatly reduce the toll of tobacco-related death and disease. Yet, data on the effects of such a policy on cigarette use among adolescents are lacking. Further, the advent of e- cigarettes and the popularity of alternative tobacco products have fundamentally altered the current landscape of nicotine delivery, and these products are widely used by adolescents. Although adolescent cigarette use is at an all-time low in the U.S., this reduction has been mirrored by an increase in e-cigarette use, and multiple tobacco product (MTP) use is the most common pattern of use in youth. Adolescent MTP users are more likely to be dependent on nicotine and to have begun using tobacco earlier than their single-product using peers. Thus, MTP-using youth differ from youth who solely smoke cigarettes in meaningful ways that have implications for responses to a nicotine reduction regulatory policy. In adults, longer-term studies have demonstrated that VLNC cigarette exposure results in fewer cigarettes smoked and reduced toxicant exposure; however, increased use of alternative tobacco products has also been reported. No studies to date have examined the effects of VLNC cigarettes on MTP use or toxicant exposure in youth. Following a one- week baseline period, we will randomize adolescent cigarette smokers (ages 15-19, N=120), who report past- month alternative tobacco product use to a four-week trial during which they will switch from usual brand cigarettes to either VLNC or normal-nicotine content (NNC, 15.8 mg/g nicotine) study cigarettes. Smoking behavior is highly influenced by individual factors such as momentary changes in withdrawal, craving, and other individual variables. Such dynamic, intra-individual and contextual factors can be assessed in the natural environment using ecological momentary assessment (EMA), which captures the influence of in-the-moment variables and reduces recall bias associated with delayed reporting. This study will use real-time, smartphone- based EMA and laboratory-based assessments to: (1) investigate the effects of cigarette nicotine reduction on cigarette and MTP use, (2) assess the influence of cigarette nicotine reduction on the harms associated with tobacco use, including nicotine and toxicant exposure, respiratory symptoms, perceived health risk and nicotine dependence, and (3) use real-time assessment to investigate the effects of nicotine reduction on changes in withdrawal and craving to characterize the mechanisms by which VLNC use may affect behavior. Overall, this project will help determine the effects of VLNC cigarettes on real-world tobacco use behavior and indices of tobacco-related harm in adolescents, and examining the mechanisms through which nicotine reduction in cigarettes may effect such changes. Such knowledge will contribute to the science base that may inform future policy decisions.